Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis

0301 basic medicine Cytotoxic T cell Receptors, Antigen, T-Cell, alpha-beta Human Inborn Errors Immunology 610 Dermatology Thymus Gland Lymphocytosis Article Mice Interferon-gamma 03 medical and health sciences In vitro T-Lymphocyte Subsets Genetic Basis of Neutropenia Disorders Biochemistry, Genetics and Molecular Biology Receptors 616 Medicine and Health Sciences Genetics T lymphocyte Animals Humans Tuberculosis Immunodeficiency Biology alpha-beta Immunology and Microbiology gamma-delta 0303 health sciences Interferon-? Pathway Defects Genetic Basis of Primary Immunodeficiency Disorders FOS: Clinical medicine Lymphocytopenia Immunity Life Sciences T cell Receptors, Antigen, T-Cell, gamma-delta CD8 T-Cell 3. Good health [SDV] Life Sciences [q-bio] Immune system Antigen FOS: Biological sciences Lymphocyte Natural Killer Cells in Immunity
DOI: 10.1084/jem.20220484 Publication Date: 2022-11-03T13:54:15Z
ABSTRACT
Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4+ αβ T lymphocytopenia with a concomitant expansion of CD4−CD8− double-negative (DN) αβ and Vδ2− γδ T lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES− phenotype. Itk-deficient mice recapitulated an expansion of the γδ T and DN αβ T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients’ T lymphocytes secrete small amounts of IFN-γ in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients’ total lymphocytes secrete small amounts of IFN-γ, and CD4+, CD8+, DN αβ T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-γ–producing T cell subsets, thereby underlying TB.
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